CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
IGFALS gene defects
Autor/es:
HORACIO M. DOMENÉ
Lugar:
San Diego, California
Reunión:
Congreso; The 92th Annual Meeting of the Endocrine Society; 2010
Institución organizadora:
The Endocrine Society
Resumen:
Title: IGFALS Gene DefectsBody: The majority of IGFs circulate in the serum as a complex with IGFBP-3 or IGFBP-5, and an acid labile subunit (ALS). The well-established function of ALS is to prolong the half-life of the IGFs-IGFBP-3/IGFBP-5 binary complexes (1). Human ALS deficiency, caused by inactivating mutations in the IGFALS gene, is characterized by moderate growth retardation and marked reduction of IGF-I and IGFBP-3 levels that remain low after GH stimulation. Since the original report of human ALS deficiency in 2004 (2), at least 21 patients have been diagnosed with this condition, suggesting that complete ALS deficiency could be more prevalent than previously suspected (3). Of the 21 patients presenting 16 different mutations in the IGFALS gene, 12 were found to be homozygous and nine were compound heterozygous. Consanguinity was present in less than half of the families. Absence of ALS protein results in the disruption of the entire IGF circulating system. Levels of IGF-I and specially IGFBP-3 are markedly reduced. Circulating IGF-II, IGFBP-1, and -2 levels are also reduced and insulin resistance is frequently observed. Despite a profound circulating IGF-I deficiency, only a mild impact on postnatal growth is observed. Perhaps, under the stimulation of normal or even increased GH levels, the local production of IGF-I could be sufficient to maintain linear growth near or within normal limits.The observation that first degree relatives heterozygous carriers (HC) for IGFALS gene mutations are frequently shorter than wild type (WT) relatives (4), suggests that heterozygous carriers for IGFALS gene mutations may have a mild growth phenotype. Two independent preliminary reports have shown a relatively high frequency of HC for IGFALS gene mutations in children with idiopathic short stature. HC patients usually exhibit decreased levels of IGF-I, IGFBP-3 and ALS. In families of ISS children, short stature and low levels of members of the IGF system segregate with HC status. These findings indicate that both gene alleles are required to maintain optimal ALS levels and to fulfill growth potential, suggesting a potential involvement of heterozygosity at the IGFALS gene in the etiology of short stature in a subset of short children presenting reduced levels of IGF-I and IGFBP-3. These studies expand the spectrum of IGFALS gene defects in children with abnormal growth and confirm the crucial role of ALS in maintaining the integrity of the circulating IGF system.References: (1) Baxter RC et al,. J Biol Chem 1989; 264:11843 (2) Domen HM et al.,N Engl J Med 2004; 350:570(3) Domen HM et al., Horm Res 2009; 72:129(4) van Duyvenvoorde HA et al., Eur J Endocrinol 2008; 159:113